The perceptions of hearing and balance originate within the complex labyrinths of the inner ear. Correct formation of the cochlea is required for the detection of sound, while correct formation and orientation of the vestibular organs is required for balance. Knowledge of the genes that promote inner ear morphogenesis will provide insights into the root causes of many human hearing and balance disorders. We have identified a novel member of the Ig superfamily, Lrig3, that is required for proper formation of the vestibular system. Lrig3 mutant mice have a truncated lateral semicircular canal (SCC) and therefore exhibit circling behavior. A detailed analysis of these mutants will shed light on the function of Lrig3 in canal formation and may reveal additional functions, as all three Lrig genes are expressed in overlapping patterns in the inner ear and in the brain. One family member, Lrig1, binds to and regulates degradation of the ErbB family of receptors, raising the possibility that Lrig3 also acts through the Erb pathway. This hypothesis will be tested with expression studies and in vitro biochemical assays. These studies will elucidate the cellular mechanisms of complex tissue morphogenesis and may reveal molecular functions for this novel family of cell surface molecules. Understanding the cellular and molecular consequences of the Lrig3 mutation in SCC morphogenesis will not only highlight the role of such molecules in inner ear development, but will also give us insight into the development of the lateral canal as it compares to the better known development of the anterior and posterior canals. While the lateral semicircular canal of Lrig3 mutants is truncated, the anterior and posterior canals, including the lateral ampulae, remain unaffected. The specificity of this defect makes Lrig3 a particularly interesting protein for study since the lateral canal is the most frequently affected structure in numerous vestibular disorders, as observed for example in patients with CHARGE syndrome. [unreadable] [unreadable] [unreadable]